Modification of the lead molecule: Tryptophan and piperidine appended triazines reversing inflammation and hyeperalgesia in rats

Priya Kumari; Sukhmeet Kaur; Jashanpreet Kaur; Rajbir Bhatti; Palwinder Singh

doi:10.1016/j.bmc.2019.115246

Modification of the lead molecule: Tryptophan and piperidine appended triazines reversing inflammation and hyeperalgesia in rats

Bioorg Med Chem. 2020 Jan 15;28(2):115246. doi: 10.1016/j.bmc.2019.115246. Epub 2019 Dec 6.

Authors

Priya Kumari¹, Sukhmeet Kaur¹, Jashanpreet Kaur², Rajbir Bhatti², Palwinder Singh³

Affiliations

¹ Department of Chemistry, Centre for Advanced Studies, Guru Nanak Dev University, Amritsar 143005, India.
² Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar 143005, India.
³ Department of Chemistry, Centre for Advanced Studies, Guru Nanak Dev University, Amritsar 143005, India. Electronic address: palwinder.chem@gndu.ac.in.

PMID: 31843462
DOI: 10.1016/j.bmc.2019.115246

Abstract

The structural optimization of the molecules making them to fit into the active site pocket of COX-2 occupying the same space as covered by the natural substrate arachidonic acid helped in the emergence of compound 10 as an efficacious anti-inflammatory agent. Selective for COX-2 over COX-1, compound 10 exhibited IC₅₀ 0.02 µM for COX-2 and reversed acetic acid induced inflammation in rats by 73% when used at 10 mg kg^-1 dose and the same dose of the compound also rescued the animals from inflammatory phase of formalin induced hyperalgesia. As evidenced by the results of molecular modeling studies supported by the nuclear Overhauser enhancement data, the appropriate geometry of the molecule in the active site pocket of COX-2 contributing to its H-bond/hydrophobic interactions with Ser530, Trp387 and Tyr385 seems responsible for the enzyme inhibitory activity of the compound.

Keywords: Anti-inflammatory; Cyclooxygenase-2; Molecular modeling; Triazine-tryptophan hybrids.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetic Acid
Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Cyclooxygenase 2 / metabolism
Cyclooxygenase 2 Inhibitors / chemical synthesis
Cyclooxygenase 2 Inhibitors / chemistry
Cyclooxygenase 2 Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Formaldehyde
Humans
Hyperalgesia / chemically induced
Hyperalgesia / drug therapy*
Hyperalgesia / metabolism
Inflammation / chemically induced
Inflammation / drug therapy*
Inflammation / metabolism
Molecular Docking Simulation
Molecular Structure
Piperidines / chemical synthesis
Piperidines / chemistry
Piperidines / pharmacology
Rats
Rats, Wistar
Structure-Activity Relationship
Triazines / chemical synthesis
Triazines / chemistry
Triazines / pharmacology
Tryptophan / chemical synthesis
Tryptophan / chemistry
Tryptophan / pharmacology

Substances

Anti-Inflammatory Agents, Non-Steroidal
Cyclooxygenase 2 Inhibitors
Piperidines
Triazines
Formaldehyde
piperidine
Tryptophan
Cyclooxygenase 2
Acetic Acid